In contrast to the cyclooxygenase inhibitors in the nonsteroidal anti-inflammatory class, acetaminophen exerts a more narrow spectrum of pharmacologic effects, acting primarily as an antipyretic and an analgesic agent with much less effect on inflammation, the platelet, and the gastrointestinal tract. Acetaminophen is known to inhibit prostaglandin production in the central nervous system and endothelial cells. We have found that the inhibition of prostaglandin biosynthesis by acetaminophen in endothelial cells was more marked when these cells were stimulated with the pyrogen, IL-l alpha, which induces both cyclooxygenase-2 and PGE2 synthase in the endothelial cell, with a resultant increase in prostacyclin and even more marked increase in the biosynthesis of PGE2. In human studies we have found that endotoxin markedly increases prostacyclin biosynthesis. From these preliminary data we postulate that acetaminophen will inhibit the biosynthesis of the prostaglandin pyrogen, PGE2, and pyrexia induced by endotoxin, and will assess this in a study with human volunteers. It is also hypothesized that during endotoxemia, acetaminophen will inhibit prostacyclin biosynthesis to a greater degree than in the control state. The effect of reducing production of this potent inhibitor of platelet aggregation on the enhanced activation of platelets in vivo during endotoxemia will be Sodium salicylate in high doses has anti-inflammatory properties. It is a weak inhibitor of purified cyclooxygenase in vitro, but has been shown to reduce prostaglandin biosynthesis in some cells. The mechanism of its antipyretic effect is unknown. We plan to determine whether an antipyretic dose of salicylate will inhibit prostaglandin biosynthesis in endotoxin-induced pyrexia, and also to assess this in relationship to the doses that exert an anti-inflammatory effect.